Project Summary/Abstract This application outlines a career development plan for the candidate who is a cerebrovascular /endovascular neurosurgeon and focuses on a profoundly important clinical problem, cerebral aneurysms, that parallels the candidate's clinical interests. The immediate goals of this project are to develop the candidate's research background and skills and increase our basic understanding of the biology of cerebral aneurysms. The long-term goals are to prepare the candidate for a life-long career as a neurosurgeon-scientist focused on cerebral aneurysms and to ultimately improve the management of patients harboring cerebral aneurysms through the development of minimally or non-invasive treatments. The candidate's primary mentor is Dr. Gary Owens, who is a leader in the investigation of molecular determinants of vascular smooth muscle cell differentiation. The candidate is also supported by an advisory committee of senior scientists and clinician-scientists (Drs. Brian Duling, Neal Kassell, Coleen McNamara and Avril Somlyo) with expertise in vascular biology, cerebral aneurysms and stroke. All key personnel have vast experience in the mentorship of trainees. Collectively, the candidate, mentor and advisory committee have formulated a career development plan that will: i.) develop the candidate's scientific background for successful research in an important area that parallels his clinical interests; ii.) facilitate the candidate's acquisition of new technical skills in cellular and molecular biology and genetics; and iii.) provide a mentored transition period between postdoctoral training and independent investigation. The plan consists of dedicated research time, attendance at meetings to present original work, attendance of academic seminars, lectures and journal clubs, formal and informal meetings with the mentor and advisory committee, as well as formal training in the responsible conduct of research. The University of Virginia's Department of Neurological Surgery provides a maximally supportive environment for the candidate's career development. The candidate was hired into a neurosurgeon-scientist full-time faculty position and all resources, infrastructure and support are in place to ensure success. The candidate has newly renovated and well equipped laboratory space, the support of clinical colleagues and support staff to ensure at least 50% of his time is protected for research and the support of an abundance of core facilities and shared resources offered through the School of Medicine and through the laboratories of the mentor and advisory committee. The University of Virginia provides the ideal environment for the candidate's career development. The main scientific focus of this proposal concerns the role of TNF- in cerebral vascular smooth muscle cell phenotypic modulation and its impact on the biology of cerebral aneurysms. Although mature vascular smooth muscle cells (SMC) are principally concerned with contraction, they retain remarkable plasticity and may undergo reversible changes in phenotype (phenotypic modulation) in response to environmental cues that can have adverse consequences. There is unequivocal evidence that SMC phenotypic modulation plays a critical role in the pathogenesis of cerebrovascular disease (such as atherosclerosis and aneurysms). SMC phenotypic modulation is characterized by transcriptional repression of SMC-marker genes (such as SM-MHC) and induction of genes involved in matrix remodeling (such as MMPs). The molecular control of SMC differentiation remains incompletely understood and virtually uninvestigated as applied to the cerebral circulation. TNF- is important in vascular disease pathogenesis, although a putative direct role in SMC phenotypic modulation has not been studied. Based upon preliminary experiments that demonstrate that TNF- induces profound phenotypic modulation in cerebrovascular SMC, the present proposal attempts to elucidate the molecular mechanisms by which TNF- directly induces SMC phenotypic modulation in vitro and also determine a potential direct role for TNF- in SMC phenotype modulation in the development and progression of cerebral aneurysms in vivo by focusing on the critical transcription factor, KLF4. This work will have direct translational applications to stroke, which lingers as the third leading cause of mortality and leading cause of disability in North America.